Recent evidence indicates that peptide-containing neurons have crucial regulatory roles in nearly every aspect of digestive function. However, the mechanisms by which peptidergic neurons interact with the classical divisions of the autonomic nervous system are largely unknown. This lack of basic information is a major obstacle to rational treatment of human enteric autonomic disorders, and is reflected in the current empiric, and often ineffective, treatment of human neuropathic disease. The current research proposal is designed to investigate, on a fundamental level, the actions of selected pancreatic neuropeptides, chosen because they demonstrate reciprocal actions within the enteropancreatic nervous system. We have hypothesized that: 1) peptide neurotransmitters regulate pancreatic function by mechanisms that act directly on acinar cells and indirectly via modulation of cholinergic neurotransmission; 2) peptide neurotransmitters activate both membrane-bound and intracellular second messenger systems; 3) acetylcholine controls neural activity via membrane- associated calcium channels; and 4) neural function is regulated, at the transcriptional level, by neuropeptide-activated calcium signalling pathways. The proposed experiments integrate physiological studies with recent advances in cellular and molecular biology. It is hoped that these studies can serve as a paradigm for other investigations of neuropeptides that affect digestive function.